Comprehensive Ablative Radiation Therapy and Immunotherapy (Avelumab) for the Treatment of Stage III-IV Merkel Cell Carcinoma, The CARTA Study

Inclusion Criteria

• Biopsy proven Merkel cell carcinoma which is unresectable or metastatic, stage III or IV
• Prior first-line treatment with aPD1 monotherapy (defined as at least one dose of pembrolizumab, avelumab, nivolumab, etc.) with evidence of progression of disease >= 10 weeks after starting therapy, in the absence of significant clinical deterioration * Patients with clinical deterioration during aPD1 monotherapy are eligible >= 6 weeks after starting aPD1 therapy ** Criteria for clinical deterioration to be determined and agreed upon by treating physician and Principal Investigator
• All detectable sites of MCC are amenable to comprehensive ablative radiation therapy in opinion of treating radiation oncologist and principal investigator
• >= 18 years of age
• Performance status =< 2 on the Eastern Cooperative Oncology Group performance scale
• Able to provide valid written informed consent
• Neutrophil count >= 1500/mm^3
• Platelet count >= 100,000/mm^3
• Hemoglobin >= 9 g/dL
• Total bilirubin =< 1.5 times the upper limit of normal, unless Gilbert’s syndrome
• Aspartate transaminase and alanine transaminase =< 2.5 times the upper limit of normal (in the absence of hepatobiliary metastases)
• =< 3.0 times the upper limit of normal (in the presence of hepatobiliary metastases)
• Estimated creatinine clearance >= 30 mL/min according to the Cockcroft-Gault formula

Exclusion Criteria

• Prior systemic therapy for MCC other than first-line aPD1 monotherapy (ie, chemotherapy)
• Pregnancy or breastfeeding
• Adverse events due to prior cancer therapy which are grade 3 or higher and have not resolved * Patients with prior grade 3 or higher immune related adverse events are not eligible, even if they have resolved
• Prior severe hypersensitivity reaction (Common Terminology Criteria for Adverse Events [CTCAE] version 5.0 grade >= 3) to avelumab
• Prior radiotherapy which precludes the ability to safely deliver comprehensive ablative radiation therapy in the opinion of the treating radiation oncologist and principal investigator * Institutional guidelines for reirradiation will be used when making this determination
• Known central nervous system metastases
• Known clinically significant cardiovascular disease, defined as: * Stroke or myocardial infarction within 6 months of first dose of avelumab * Symptomatic congestive heart failure (New York Heart Association class 2 or higher) * Serious arrhythmia requiring anti-arrhythmic agents
• Known human immunodeficiency virus infection
• Known hepatitis B or C infection requiring ongoing treatment
• Vaccination within 4 weeks of first dose of avelumab * Inactivated vaccines are permissible
• Iatrogenic immunosuppression with daily systemic corticosteroid equivalent of > 10 mg of prednisone
• Active autoimmune disease that may cause clinical deterioration during immunotherapy * Including, but not limited to: ** Inflammatory bowel disease or immune colitis ** Immune mediated pneumonitis or pulmonary fibrosis
• History of solid organ or hematopoietic transplant
• Active infection requiring systemic therapy
• Active suicidal ideation or behavior
• Comorbid or diagnostic abnormalities which would interfere with interpretation of study results
• Known hematopoietic cancer or dysfunction (i.e., leukemia, lymphoma)
• Known non-MCC solid tumor with known metastasis or estimated risk of metastasis > 20% within 3 months